This invention was made with the assistance of National Institute on Aging grant number AGO7591. The Government has certain rights in this invention.
Alzheimer's disease (AD) affects approximately 5-15% of the population of the U.S. over age 65 (1.2-4 million). This disease is frequently associated with individuals over the age of 60 and is the most frequent cause of institutionalization for long-term care. In 1983, more than $27 billion was spent in the U.S. in health care for Alzheimer's afflicted individuals.
Six basic areas of investigation have been defined by R. J. Wurtman, Scientific Amer., 62, (1988), as underlying most research on the causes of Alzheimer's disease. These areas include faulty genes, accumulations of amyloid protein, infectious agents, environmental toxins (e.g., aluminum and certain unusual amino acids), inadequate blood flow and energy metabolism, and lastly cholinergic deficits.
A number of possible therapeutic interventions are currently under study. These include the use of nerve growth factors (NGF), muscarinic and nicotinic agonists, acetylcholinesterase (AChE) inhibitors, GABA-inverse agonists, NMDA modulators, and others. It is, however, unlikely that any single drug will restore cognition, especially in view of the involvement of a number of different neurotransmitter systems in memory processing, and the fact that dead neurons cannot be revived.
To the extent that AChE inhibitors ran serve as useful adjuncts in the treatment of AD, two relatively new lycopodium alkaloids, huperzine A and B, isolated from Huperzia serrata (Thunb.) Trev., a Chinese folk medicine, appear superior to THA and physostigmine. J. S. Liu et al., Can. J. Chem., 64, 837 (1986); W. A. Ayer et al., ibid., 67, 1077 (1989), ibid., 67, 1538 (1989). In studies performed in China, these compounds have been found to improve memory and learning in animals. X. C. Tang et al., Acta Pharmacol. Sinica, 7, 507 (1986). Additionally, huperzine A has been studied by workers at Hoffmann LaRoche in mice and squirrel monkeys, and the compound has been found to be an effective cognition enhancer. G. P. Vincent et al., Neurosci. Abst., 13, 884 (1987). The duration of action of a single dose (2 mg/kg i.m.) of huperzine A is over 6 hr, a remarkable result in relation to the AChE inhibitory action of physostigmine (0.65 mg/kg i.m.), which has a maximal duration of action of 60 min and which causes considerable side effects. X. C. Tang et al., J. Neurosci. Res., 24, 276 (1989). Huperzine A has further been tested in 128 patients suffering from myasthenia gravis and found to control the clinical manifestations of the disease in 99% of these cases. Y.-S. Cheng, New Drugs and Clinical Remedies, 5, 197 (1986).
Analogs of huperzine A have been reported. For example, A. P. Kozikowski et al. (U.S. Pat. No. 4,929,731) disclose the analog of huperzine A, wherein the amino group has been replaced by --CH.sub.2 NH.sub.2. However, this analog was about 166 times less potent than (.+-.)-huperzine A as an inhibiter of AChE. Therefore, a continuing need exists for analogs of huperzine which exhibit improved potency, high metabolic stability, better partitioning into the brain, and/or a longer duration of action.